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CHAPTER OBJECTIVES

  • Define the index for measuring drug accumulation.

  • Define drug accumulation and drug accumulation t1/2.

  • Explain the principle of superposition and its assumptions in multiple-dose regimens.

  • Calculate the steady-state Cmax and Cmin after multiple IV bolus dosing of drugs.

  • Calculate k and VD of aminoglycosides in multiple-dose regimens.

  • Adjust the steady-state Cmax and Cmin in the event the last dose is given too early, too late, or totally missed following multiple IV dosing.

INTRODUCTION

Earlier chapters of this book discussed single-dose drug and constant-rate drug administration. By far though, most drugs are given in several doses, for example, multiple doses to treat chronic disease such as arthritis, hypertension, etc. After single-dose drug administration, the plasma drug level rises above and then falls below the minimum effective concentration (MEC), resulting in a decline in therapeutic effect. To treat chronic disease, multiple-dosage or IV infusion regimens are used to maintain the plasma drug levels within the narrow limits of the therapeutic window (eg, plasma drug concentrations above the MEC but below the minimum toxic concentration or MTC) to achieve optimal clinical effectiveness. These drugs may include antibacterials, cardiotonics, anticonvulsants, hypoglycemics, antihypertensives, hormones, and others. Ideally, a dosage regimen is established for each drug to provide the appropriate plasma level without excessive fluctuation and drug accumulation outside the desired therapeutic window.

For certain drugs, such as antibiotics, a desirable MEC can be determined. For drugs that have a narrow therapeutic range (eg, digoxin and phenytoin), there is a need to define the therapeutic minimum and maximum nontoxic plasma concentrations (MEC and MTC, respectively). In calculating a multiple-dose regimen, the desired or target plasma drug concentration must be related to a therapeutic response, and the multiple-dose regimen must be designed to produce plasma concentrations within the therapeutic window.

There are two main parameters that can be adjusted in developing a dosage regimen: (1) the size of the drug dose and (2) τ, the frequency of drug administration (ie, the time interval between doses).

DRUG ACCUMULATION

To calculate a multiple-dose regimen for a patient or patients, pharmacokinetic parameters are first obtained from the plasma level–time curve generated by single-dose drug studies. With these pharmacokinetic parameters and knowledge of the size of the dose and dosage interval (τ), the complete plasma level–time curve or the plasma level may be predicted at any time and any number of doses after the beginning of the dosage regimen. For simplicity, this chapter assumes a one-compartment model and linear pharmacokinetics. For a multicompartmental drug, pharmacokinetic parameters are calculated simply using a pharmacokinetic model and software to predict the drug concentrations.

For calculation of multiple-dose regimens, it is necessary to determine whether successive doses of drug will have any effect on the previous dose. The principle of ...

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